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1. Milk polar lipids favorably alter circulating and intestinal ceramide and sphingomyelin species in postmenopausal women

Author

Mélanie Le Barz, Cécile Vors, Emmanuel Combe, Laurie Joumard-Cubizolles, Manon Lecomte, Florent Joffre, Michèle Trauchessec, Sandra Pesenti, Emmanuelle Loizon, Anne-Esther Breyton, Emmanuelle Meugnier, Karène Bertrand, Jocelyne Drai, Chloé Robert, Annie Durand, Charlotte Cuerq, Patrice Gaborit, Nadine Leconte, Annick Bernalier-Donadille, Eddy Cotte, Martine Laville, Stéphanie Lambert-Porcheron, Lemlih Ouchchane, Hubert Vidal, Corinne Malpuech-Brugère, David Cheillan, and Marie-Caroline Michalski

Subjects
Clinical trials, Metabolism, Medicine
Abstract

BACKGROUND High circulating levels of ceramides (Cer) and sphingomyelins (SM) are associated with cardiometabolic diseases. The consumption of whole fat dairy products, naturally containing such polar lipids (PL), is associated with health benefits, but the impact on sphingolipidome remains unknown.METHODS In a 4-week randomized controlled trial, 58 postmenopausal women daily consumed milk PL-enriched cream cheese (0, 3, or 5 g of milk PL). Postprandial metabolic explorations were performed before and after supplementation. Analyses included SM and Cer species in serum, chylomicrons, and feces. The ileal contents of 4 ileostomy patients were also explored after acute milk PL intake.RESULTS Milk PL decreased serum atherogenic C24:1 Cer, C16:1 SM, and C18:1 SM species (Pgroup < 0.05). Changes in serum C16+18 SM species were positively correlated with the reduction of cholesterol (r = 0.706), LDL-C (r = 0.666), and ApoB (r = 0.705) (P < 0.001). Milk PL decreased chylomicron content in total SM and C24:1 Cer (Pgroup < 0.001), parallel to a marked increase in total Cer in feces (Pgroup < 0.001). Milk PL modulated some specific SM and Cer species in both ileal efflux and feces, suggesting differential absorption and metabolization processes in the gut.CONCLUSION Milk PL supplementation decreased atherogenic SM and Cer species associated with the improvement of cardiovascular risk markers. Our findings bring insights on sphingolipid metabolism in the gut, especially Cer, as signaling molecules potentially participating in the beneficial effects of milk PL.TRIAL REGISTRATION ClinicalTrials.gov, NCT02099032, NCT02146339.FUNDING ANR-11-ALID-007-01; PHRCI-2014: VALOBAB, no. 14-007; CNIEL; GLN 2018-11-07; HCL (sponsor).

Published
2021
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2. Milk polar lipids favorably alter circulating and intestinal ceramide and sphingomyelin species in postmenopausal women

Author

Chloé Robert, Marie-Caroline Michalski, Nadine Leconte, Manon Lecomte, Laurie Joumard-Cubizolles, David Cheillan, Karène Bertrand, Anne-Esther Breyton, Emmanuel Combe, Annie Durand, Mélanie Le Barz, Florent Joffre, Martine Laville, Corinne Malpuech-Brugère, Cécile Vors, Michèle Trauchessec, Lemlih Ouchchane, Charlotte Cuerq, Sandra Pesenti, Patrice Gaborit, Hubert Vidal, Eddy Cotte, Jocelyne Drai, Stéphanie Lambert-Porcheron, Emmanuelle Meugnier, Emmanuelle Loizon, Annick Bernalier-Donadille, Cardiovasculaire, métabolisme, diabétologie et nutrition (CarMeN), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Unité de Nutrition Humaine (UNH), Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Clermont Auvergne (UCA), Institut des Corps Gras, (ITERG), Hospices Civils de Lyon, Unité Maladies Héréditaires du Métabolisme, Service de Biochimie et Biologie, Centre, Hospices Civils de Lyon, Unité de Nutrition Endocrinologie Métabolisme, Service de Biochimie, ACTALIA, Dairy Products and Technologies, Science et Technologie du Lait et de l'Oeuf (STLO), AGROCAMPUS OUEST, Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Microbiologie Environnement Digestif Santé (MEDIS), Hospices Civils de Lyon, Centre Hospitalier Lyon-Sud, Pierre-Bénite, Service de Chirurgie Digestive, Centre de Recherche en Nutrition Humaine Rhône-Alpes (CRNH-RA), Université Grenoble Alpes (UGA)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-CHU Grenoble-Hospices Civils de Lyon (HCL)-CHU Saint-Etienne-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Unité de Biostatistiques [CHU Clermont-Ferrand], Direction de la recherche clinique et de l’innovation [CHU Clermont-Ferrand] (DRCI), CHU Clermont-Ferrand-CHU Clermont-Ferrand, FUNDINGS. Agence Nationale de la Recherche, ANR-11-ALID-007-01, Regional Hospital Clinical Research Program (PHRCI-2014: VALOBAB, n°14-007), French Dairy Interbranch Organization (CNIEL), Groupe Lipides et Nutrition (GLN 2018-11-07), Hospices Civils de Lyon as sponsor., Giboulot, Anne, Actalia - division produits laitiers, Actalia [Saint-Lô], Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-INSTITUT AGRO Agrocampus Ouest, Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro), Université de Lyon-Université de Lyon-CHU Grenoble-Hospices Civils de Lyon (HCL)-CHU Saint-Etienne-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Grenoble Alpes (UGA), Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E)-Université Claude Bernard Lyon 1 (UCBL), and Université de Lyon-Université de Lyon-CHU Grenoble-Hospices Civils de Lyon (HCL)-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Grenoble Alpes (UGA)

Subjects
0301 basic medicine, chemistry.chemical_compound, Feces, 0302 clinical medicine, Cheese, maladie cardiovasculaire, Gastrointestinal tract, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, food and beverages, General Medicine, Cardiovascular disease, 3. Good health, Sphingomyelins, Postmenopause, Postprandial, Cholesterol, Milk, 030220 oncology & carcinogenesis, lipide polaire, Female, lipids (amino acids, peptides, and proteins), Sphingomyelin, medicine.medical_specialty, Ceramide, sphingomyéline, Ceramides, 03 medical and health sciences, intestin, Internal medicine, medicine, Animals, Humans, Clinical Trials, Lipid rafts, Glycoproteins, business.industry, lipide du lait, ménopause, Metabolism, Lipid Droplets, Overweight, Lipid Metabolism, Diet, [SDV.AEN] Life Sciences [q-bio]/Food and Nutrition, 030104 developmental biology, Endocrinology, chemistry, Clinical Medicine, Glycolipids, business, [SDV.AEN]Life Sciences [q-bio]/Food and Nutrition, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Chylomicron
Abstract

International audience; BACKGROUND. High circulating levels of ceramides (Cer) and sphingomyelins (SM) have been associated with cardiometabolic diseases. The consumption of whole-fat dairy products, which naturally contain such polar lipids (PL), is associated with health benefits, but the impact on sphingolipidome remains unknown. We investigated how milk PL supplementation impacts circulating and intestinal SM and Cer composition in association with improvement of cardiovascular markers.METHODS. In a 4 week-randomized double-blind controlled study, 58 postmenopausal women consumed daily a cream cheese containing 0, 3 or 5 g of milk PL. Postprandial metabolic explorations were performed before and after the supplementation. SM and Cer species were analyzed in serum, intestine-derived chylomicrons and feces. The ileal content of 4 ileostomy patients was also explored after milk PL intake in a crossover double-blind study.RESULTS. Milk PL consumption decreased serum atherogenic C24:1 Cer (Pgroup = 0.033), C16:1 (Pgroup = 0.007) and C18:1 (Pgroup = 0.003) SM species. Changes in serum C16+18 SM species were positively correlated with the reduction of total cholesterol (r = 0.706, P < 0.001), LDL-C (r = 0.666, P < 0.001) and ApoB (r = 0.705, P < 0.001). Milk PL decreased the concentration in chylomicrons of total SM (Pgroup < 0.0001) and of C24:1 Cer (Pgroup = 0.001). Saturated SM and Cer species, which are also the major species found in milk PL-enriched cheeses, increased in ileal efflux and feces. There was a marked increase in total fecal Cer after milk PL supplementation (Pgroup = 0.0002). Milk PL also modulated the abundance of some specific SM and Cer species in ileal efflux and feces, suggesting differential absorption and metabolization processes in the gut.CONCLUSION. These data demonstrate that milk PL supplementation decreases atherogenic SM and Cer species associated with an improvement of cardiovascular risk markers. Our findings bring new insights on sphingolipid metabolism in the gastrointestinal tract, especially Cer as such signaling molecules potentially participating in the beneficial effect of milk PL. ClinicalTrials.gov, NCT02099032, NCT02146339.

Published
2021
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3. Milk Polar Lipids Reduce Cholesterolemia by Decreasing Cholesterol Absorption in Humans (P06-041-19)

Author

Corinne Malpuech-Brugère, Cécile Vors, Laurie Joumard-Cubizolles, Lemlih Ouchchane, Stéphanie Lambert-Porcheron, K. Raynal, Marie-Caroline Michalski, Martine Laville, Geneviève Gésan-Guiziou, Florent Joffre, Laure Meiller, Manon Lecomte, Eddy Cotte, Emmanuel Combe, Emilie Blond, Mélanie Le Barz, Jocelyne Drai, Patrice Gaborit, Cardiovasculaire, métabolisme, diabétologie et nutrition (CarMeN), Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Institut National de la Recherche Agronomique (INRA), Unité de Nutrition Humaine (UNH), Institut National de la Recherche Agronomique (INRA)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), Hospices Civils de Lyon (HCL), Centre de Recherche en Nutrition Humaine, Institut des corps gras (ITERG), ENILIA-ENSMIC, Actalia, Science et Technologie du Lait et de l'Oeuf (STLO), Institut National de la Recherche Agronomique (INRA)-AGROCAMPUS OUEST, Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro), Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), Université de Lyon (COMUE), American Society for Nutrition., ProdInra, Migration, Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Actalia [Saint-Lô]

Subjects
0301 basic medicine, medicine.medical_specialty, Diet therapy, [SPI.GPROC] Engineering Sciences [physics]/Chemical and Process Engineering, [SDV]Life Sciences [q-bio], Medicine (miscellaneous), Blood lipids, 030209 endocrinology & metabolism, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, diet therapy, ldl cholesterol lipoproteins, high density lipoprotein, cholesterol cardiovascular disease risk, Internal medicine, [SDV.IDA]Life Sciences [q-bio]/Food engineering, medicine, [SPI.GPROC]Engineering Sciences [physics]/Chemical and Process Engineering, 2. Zero hunger, 030109 nutrition & dietetics, Nutrition and Dietetics, Cholesterol, Dietary Bioactive Components, [SDV.IDA] Life Sciences [q-bio]/Food engineering, Crossover study, 3. Good health, Coprostanol, [SDV] Life Sciences [q-bio], Postprandial, Endocrinology, chemistry, Intestinal cholesterol absorption, lipids (amino acids, peptides, and proteins), Food Science, Chylomicron
Abstract

Objectives: Nutritional strategies can play a major role in the management of cholesterolemia, notably in postmenopausal women at risk of CVD. Interest has recently grown on the potential health benefits of milk polar lipids (MPL).We showed that isolipidic enrichment of the diet with MPL improved several lipid CV risk factors but underlying mechanisms remained unclear. We hypothesized that MPL reduce intestinal cholesterol absorption in humans. Methods:We performed a double-blind randomized controlled trial in 58 postmenopausal women with fasting HDL-cholesterol < 1.6 mM.They were subjected to a 4-week dietary intervention with daily consumption of a cream-cheese containing 12 g of milk fat including either 0 g (control, n = 19), 3 g (n = 19) or 5 g (n = 20) of MPL. Before and after each intervention, blood lipids were measured in the whole cohortwhereas fecal lipids and coprostanol were analyzed in a subgroup (n = 7–9 per group). A proof-of-concept mechanistic crossover study was also carried out in 4 ileostomized subjects who performed 8hpostprandial tests after consuming 0g-, 3g- or 5g-MPL enriched cheese labelled with 2H-cholesterol tracer. Plasma, chylomicrons and ileal efflux were analyzed. Results: Milk fat enriched with 3 to 5 g MPL induced doseresponse reductions in serum total cholesterol (up to −6.8% in 5 g group, p < 0.05), LDL-cholesterol (−8.7%, p < 0.05) and HDL/total-cholesterol ratio (p < 0.001), compared to the control that had no effect. Fecal excretion of coprostanol increased after MPL supplementation (p < 0.05, 3g- and 5g-MPL vs control), and the fecal coprostanol/cholesterol ratio was inversely correlated with serum total- and LDL-cholesterol after intervention (r = −0.5, p < 0.05). In ileostomized subjects, postprandial accumulation of 2Hcholesterol in plasma and chylomicrons was reduced after 3 to 5 g MPL consumption (p < 0.05, vs control). Both cholesterol and milk sphingomyelin increased in ileal efflux after MPL enriched cheeses (p < 0.05). Conclusions: Present results suggest that milk polar lipids decrease cholesterol absorption in humans through interactions with sphingomyelin and by increasing conversion of cholesterol to coprostanol. Funding Sources: ANR (French National Research Agency, VALOBAB project, ANR-11-ALID-007–01), PHRC-I (French Clinical Research Program, 14–007), CNIEL (French Dairy Interbranch Organization).

Published
2019
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4. Les lipides polaires laitiers diminuent les facteurs lipidiques du risque cardiovasculaire chez des femmes ménopausées

Author

Corinne Malpuech-Brugère, Cécile Vors, Florent Joffre, Patrice Gaborit, Martine Laville, Adeline Blot, Lemlih Ouchchane, J. Drai, Laurie Joumard-Cubizolles, K. Raynal, Emmanuel Combe, Marie-Caroline Michalski, Geneviève Gésan-Guiziou, S. Lambert-Porcheron, Cardiovasculaire, métabolisme, diabétologie et nutrition (CarMeN), Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hospices Civils de Lyon (HCL), Unité de Nutrition Humaine - Clermont Auvergne (UNH), Institut National de la Recherche Agronomique (INRA)-Université Clermont Auvergne (UCA), UCA UMR6602, SIGMA, CRNH Rhône-Alpes, ACTALIA, ENILIA, ENILIA, Actalia, Institut des Corps Gras (ITERG), CRNH Auvergne, CHU, Science et Technologie du Lait et de l'Oeuf (STLO), Institut National de la Recherche Agronomique (INRA)-AGROCAMPUS OUEST, CRNH Rhône-Alpes, HCL, UMR : Unité de Nutrition Humaine, Saint-Genes-Champanelle, Institut National de la Recherche Agronomique (INRA), Etude financée par l’ANR (projet VALOBAB, ANR-11-ALID-007-01, coord. MC Michalski), le PHRC-I (n°14-007, coord. clinique S. Lambert-Porcheron) et le CNIEL., Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM), Unité de Nutrition Humaine (UNH), Institut National de la Recherche Agronomique (INRA)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), Institut Pascal (IP), SIGMA Clermont (SIGMA Clermont)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Centre National de la Recherche Scientifique (CNRS), Actalia [Saint-Lô], SIGMA Clermont (SIGMA Clermont)-Centre National de la Recherche Scientifique (CNRS)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro), ProdInra, Archive Ouverte, Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université Claude Bernard Lyon 1 (UCBL), and Université de Lyon-Institut National de la Recherche Agronomique (INRA)

Subjects
0303 health sciences, Nutrition and Dietetics, 030309 nutrition & dietetics, Endocrinology, Diabetes and Metabolism, ménopause, [SDV.IDA] Life Sciences [q-bio]/Food engineering, allégations nutritionnelles et de santé, produit laitier, 3. Good health, [SDV.AEN] Life Sciences [q-bio]/Food and Nutrition, 03 medical and health sciences, 0302 clinical medicine, nutrition, dairy product, cardiovascular disease, 030220 oncology & carcinogenesis, risque cardivasculaire, maladie cardiovasculaire, femme menopausée, [SDV.IDA]Life Sciences [q-bio]/Food engineering, Internal Medicine, lipide polaire, [SDV.AEN]Life Sciences [q-bio]/Food and Nutrition
Abstract

communication orale et poster présentés aux Journées francophone de nutrition de Nice, du 28 au 30 novembre 2018; Introduction et but de l’étudeDes perturbations du métabolisme lipidique à jeun et en phase postprandiale constituent des facteurs de risque cardiovasculaire. La nutrition joue un rôle majeur dans leur modulation, notamment chez les femmes ménopausées qui constituent une population à risque. Un intérêt s’est récemment développé sur les effets bénéfiques potentiels des lipides polaires (LP) laitiers, qui sont riches en sphingomyéline. A ce jour, leurs effets chez l’Homme restent cependant à clarifier, car les rares études cliniques ont jusqu’à présent été réalisées chez des sujets sains et par supplémentation, augmentant ainsi l’apport énergétique. Nous avons donc testé l’hypothèse qu’un enrichissement isolipidique de l’alimentation avec des LP laitiers apportés par un produit laitier réaliste pourrait améliorer le profil cardiovasculaire de femmes ménopausées à risque.Matériel et méthodesUn essai clinique contrôlé aléatoire en double aveugle chez 58 femmes ménopausées en surpoids a été réalisé. Les volontaires ont été soumises à (i) 4 semaines d’intervention avec consommation quotidienne d’un fromage à tartiner contenant 12g de matière grasse laitière incluant aléatoirement soit 0g (contrôle, n=19), 3g (n=19) ou 5g (n=20) de LP laitiers, et (ii) des tests d’exploration métabolique sur 8h, avant et après intervention (2 visites). Des marqueurs lipidiques ont été mesurés dans le sérum et dans la fraction riche en chylomicrons. L’effet de la dose de LP laitiers a été testé par un modèle linéaire mixte (SAS®) recherchant les différences entre visites et entre groupes d’intervention.Résultats et analyse statistiqueLa consommation du fromage à 5g-LP diminue les concentrations sériques à jeun et postprandiales du cholestérol total (−0,33±0,03mM, p

Published
2019
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5. DHA-derived oxylipins, neuroprostanes and protectins, differentially and dose-dependently modulate the inflammatory response in human macrophages: putative mechanisms through PPAR activation

Author

Nathalie Hennuyer, Laurie Joumard-Cubizolles, Jean-Marie Galano, Corinne Copin, Giuseppe Zanoni, Camille Oger, Alessio Porta, Andrzej Mazur, Thierry Durand, Rémy Bosviel, Cécile Gladine, Giulia Chinetti-Gbaguidi, Dominique Bayle, Bart Staels, Isabelle Duplan, Laurence Balas, Unité de Nutrition Humaine (UNH), Institut National de la Recherche Agronomique (INRA)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), Récepteurs nucléaires, maladies cardiovasculaires et diabète - U 1011 (RNMCD), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Lille, Centre Hospitalier Universitaire de Lille (CHU de Lille), European Genomic Institute for Diabetes - FR 3508 (EGID), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), Institute of research on Cancer and Aging (IRCAN), Université de Nice Sophia-Antipolis (UNSA), Centre National de la Recherche Scientifique (CNRS), Réseau International des Instituts Pasteur (RIIP), Università degli Studi di Pavia, Institut des Biomolécules Max Mousseron [Pôle Chimie Balard] (IBMM), Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)-Université de Montpellier (UM)-Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM), Université de Montpellier (UM), Ecole Nationale Supérieure de Chimie de Montpellier, INRA - Human nutrition department and the French Research on Lipids & Nutrition Group (GLN), Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Institut Européen de Génomique du Diabète - European Genomic Institute for Diabetes - FR 3508 (EGID), Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), Università degli Studi di Pavia = University of Pavia (UNIPV), Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM)-Institut de Chimie du CNRS (INC)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM), ProdInra, Archive Ouverte, Unité de Nutrition Humaine - Clermont Auvergne (UNH), Institut National de la Recherche Agronomique (INRA)-Université Clermont Auvergne (UCA), Récepteurs nucléaires, maladies cardiovasculaires et diabète (EGID), Université de Lille, Droit et Santé-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), European Genomic Institute for Diabetes [Lille] (EGID), Università di Pavia, and Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)

Subjects
0301 basic medicine, Lipopolysaccharides, [SDV.BIO]Life Sciences [q-bio]/Biotechnology, Anti-Inflammatory Agents, Drug Evaluation, Preclinical, Peroxisome proliferator-activated receptor, Gene Expression, Protectins, Pharmacology, Biochemistry, Lipoxygenase, Transactivation, 0302 clinical medicine, Chlorocebus aethiops, Cells, Cultured, chemistry.chemical_classification, [SDV.MHEP.EM] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, biology, Chemistry, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, DHA, Docosahexaenoic acid, 030220 oncology & carcinogenesis, COS Cells, Cytokines, medicine.symptom, Docosahexaenoic Acids, PPARs, Lipid mediators, Inflammation, Omega 3 PUFAs, macrophage humain, 03 medical and health sciences, Physiology (medical), medicine, Animals, Humans, Neuroprostanes, Oxylipins, activité anti-inflammatoire, Dose-Response Relationship, Drug, Macrophages, Lipid signaling, acide gras oméga 3, [SDV.BIO] Life Sciences [q-bio]/Biotechnology, IκBα, [SDV.AEN] Life Sciences [q-bio]/Food and Nutrition, 030104 developmental biology, oxylipine, biology.protein, Free-radical mediated oxygenation, [SDV.AEN]Life Sciences [q-bio]/Food and Nutrition
Abstract

Whereas the anti-inflammatory properties and mechanisms of action of long chain ω3 PUFAs have been abundantly investigated, research gaps remain regarding the respective contribution and mechanisms of action of their oxygenated metabolites collectively known as oxylipins. We conducted a dose-dependent and comparative study in human primary macrophages aiming to compare the anti-inflammatory activity of two types of DHA-derived oxylipins including the well-described protectins (NPD1 and PDX), formed through lipoxygenase pathway and the neuroprostanes (14-A4t- and 4-F4t-NeuroP) formed through free-radical mediated oxygenation and expected to be new anti-inflammatory mediators. Considering the potential ability of these DHA-derived oxylipins to bind PPARs and knowing the central role of these transcription factors in the regulation of macrophage inflammatory response, we performed transactivation assays to compare the ability of protectins and neuroprostanes to activate PPARs. All molecules significantly reduced mRNA levels of cytokines such as IL-6 and TNF-α, however not at the same doses. NPD1 showed the most effect at 0.1µM (-14.9%, p

Published
2017
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6. The omega-3 fatty acid docosahexaenoic acid favorably modulates the inflammatory pathways and macrophage polarization within aorta of LDLR-/- mice

Author

Marie-Anne Verny, Laurie Joumard-Cubizolles, Andrzej Mazur, Blandine Comte, Cécile Gladine, Monika Zmojdzian, Unité de Nutrition Humaine (UNH), Institut National de la Recherche Agronomique (INRA)-Université d'Auvergne - Clermont-Ferrand I (UdA)-Clermont Université, and intramural French National Institute for Agricultural Research (INRA)

Subjects
chemistry.chemical_classification, medicine.medical_specialty, Innate immune system, Endocrinology, Diabetes and Metabolism, macrophage polarization, [SDV]Life Sciences [q-bio], Macrophage polarization, omega-3 fatty acid, Fatty acid, Inflammation, Biology, M2 Macrophage, Endocrinology, chemistry, Docosahexaenoic acid, Internal medicine, Immunology, Genetics, medicine, medicine.symptom, atherosclerosis, Omega 3 fatty acid, microarray, Research Paper, Polyunsaturated fatty acid
Abstract

International audience; The omega-3 fatty acid docosahexaenoic acid (DHA) has potent anti-atherogenic properties but its mechanisms of action at the vascular level remain poorly explored. Knowing the broad range of molecular targets of omega-3 fatty acids, microarray analysis was used to open-mindedly evaluate the effects of DHA on aorta gene expression in LDLR-/- mice and better understand its local anti-atherogenic action. Mice were fed an atherogenic diet and received daily oral gavages with oils rich in oleic acid or DHA. Bioinformatics analysis of microarray data first identified inflammation and innate immunity as processes the most affected by DHA supplementation within aorta. More precisely, several down-regulated genes were associated with the inflammatory functions of macrophages (e. g., CCL5 and CCR7), cell movement (e. g., ICAM-2, SELP, and PECAM-1), and the major histocompatibility complex (e. g., HLA-DQA1 and HLA-DRB1). Interestingly, several genes were identified as specific biomarkers of macrophage polarization, and their changes suggested a preferential orientation toward a M2 reparative phenotype. This observation was supported by the upstream regulator analysis highlighting the involvement of three main regulators of macrophage polarization, namely PPAR gamma (z-score = 2.367, p = 1.50 x 10(-13)), INF gamma (z-score = -2.797, p = 2.81 x 10(-14)), and NF kappa B (z-score = 2.360, p = 6.32 x 10(-9)). Moreover, immunohistological analysis of aortic root revealed an increased abundance of Arg1 (+111 %, p = 0.01), a specific biomarker of M2 macrophage. The present study showed for the first time that DHA supplementation during atherogenesis is associated with protective modulation of inflammation and innate immunity pathways within aorta putatively through the orientation of plaque macrophages toward a M2 reparative phenotype.

Published
2014
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